title: Structure analysis reveals the flexibility of the ADAMTS-5 active site.
abstract: A ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) succinamide derivative (here referred to as Compound 12) shows significant activity toward many matrix metalloproteinases (MMPs), including MMP-2, MMP-8, MMP-9, and MMP-13. Modeling studies had predicted that this compound would not bind to ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs-5) due to its shallow S1' pocket. However, inhibition analysis revealed it to be a nanomolar inhibitor of both ADAMTS-4 and -5. The observed inconsistency was explained by analysis of crystallographic structures, which showed that Compound 12 in complex with the catalytic domain of ADAMTS-5 (cataTS5) exhibits an unusual conformation in the S1' pocket of the protein. This first demonstration that cataTS5 can undergo an induced conformational change in its active site pocket by a molecule like Compound 12 should enable the design of new aggrecanase inhibitors with better potency and selectivity profiles.
authors.affiliation: Pfizer Global Research and Development, St. Louis, Missouri 63017, USA. shiehouse@sbcglobal.net
authors.forename: Huey-Sheng
authors.initials: HS
authors.lastname: Shieh
authors.forename: Alfredo G
authors.initials: AG
authors.lastname: Tomasselli
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Mathis
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schnute
authors.forename: Scott S
authors.initials: SS
authors.lastname: Woodard
authors.forename: Nicole
authors.initials: N
authors.lastname: Caspers
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Williams
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.forename: Grace
authors.initials: G
authors.lastname: Munie
authors.forename: Arthur
authors.initials: A
authors.lastname: Wittwer
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Malfait
authors.forename: Micky D
authors.initials: MD
authors.lastname: Tortorella
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry*; D000071116:ADAMTS5 Protein; D000577:Amides / Q000737:chemistry*; D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D015195:Drug Design; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D013386:Succinates
chemical_list: D000577:Amides; D061965:Matrix Metalloproteinase Inhibitors; D013386:Succinates; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D020782:Matrix Metalloproteinases; C011116:succinamide